Mechanisms of Stroke in Intracranial Stenosis and Stenting (MoSISS) This proposal is a prospective multi-center ancillary study to SAMMPRIS, an ongoing NIH- funded trial that evaluates intracranial stenting plus intensive medical therapy versus intensive medical therapy alone for recently symptomatic high-grade intracranial stenosis. The objective of this application is to understand the mechanisms that underlie ischemic stroke in stented and non-stented patients, as mechanistic aspects and related imaging analyses are not incorporated in SAMMPRIS. The results of this proposal will help define the appropriate parameters that predict stroke risk and may lead to novel therapeutics to address specific mechanisms of stroke. Our primary hypothesis is that several mechanisms underlie ischemic infarction in intracranial atherosclerosis. This proposal will evaluate 6 specific mechanisms of stroke in a sample of the SAMMPRIS cohort: decreased antegrade flow, progression of stenosis, decreased proximal collateral flow, decreased distal collateral flow, impaired cerebrovascular reserve, and artery-artery embolism. The main outcome will be ischemic stroke occurrence in the territory of the symptomatic artery, a principal endpoint in the SAMMPRIS study. A total of 100 medically-treated and 50 stented patients enrolled in the SAMMPRIS study will be studied with 3 imaging modalities, including: a) conventional angiography performed prior to randomization in SAMMPRIS;b) baseline QMRA to assess volumetric flow rate as a marker of antegrade flow and proximal collateral flow;c) serial TCD to measure flow velocities at baseline, 4, 8, 12 and 24 months, and at the time of ischemic stroke occurrence;d) baseline TCD to detect embolic signals in patients with intracranial carotid or middle cerebral artery stenosis;and e) baseline TCD with breath-holding to assess vasomotor reactivity in patients with intracranial carotid or middle cerebral artery stenosis. PUBLIC HEALTH RELEVANCE: Lay Summary: Mechanisms of Stroke in Intracranial Stenosis and Stenting (MoSISS) MoSISS is an ancillary study to the ongoing Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis (SAMMPRIS) study. Narrowing of the brain arteries due to plaque formation (intracranial atherosclerotic disease) is a common cause of stroke. The risk of stroke recurrence is significant, particularly in those with greater than 70% narrowing, even with medical therapy. Because of this, SAMMPRIS is evaluating stenting plus intensive medical therapy vs. intensive medical therapy alone. The objective of this proposal is to understand the causes of stroke in those with narrowed brain arteries and stented brain arteries through the use of non-invasive imaging tests such as ultrasound and MRI.